| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Open-Angle Glaucoma
or Ocular Hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
Open-Angle Glaucoma
or Ocular Hypertension |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to demonstrate that the mean intraocular
pressure (IOP) reduction after 3 months (90 days) of treatment with
BOL-303259-X 0.024% (latanoprostene bunod) once daily (QD) is
non-inferior to timolol maleate 0.5% twice daily (BID). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective is to demonstrate the superiority of
BOL-303259-X 0.024% QD to timolol maleate 0.5% BID. This
assessment will be performed if the non-inferiority of BOL-303259-X
0.024% QD to timolol maleate 0.5% BID is determined. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must be of legal age (at least 18 years) on the date the Informed Consent Form (ICF) is signed and with the capacity to provide voluntary informed consent.
2. Subjects must be able to read, understand, and provide written informed consent on the Institutional Review Board/Ethics Committee-approved ICF and provide authorization as appropriate for local privacy regulations.
3. Subjects who are able and willing to comply with all treatment and follow-up/study procedures.
4. Subjects who are not of childbearing potential or female subjects who have a negative urine pregnancy test result at Visit 1 (Screening) and Visit 3 (Eligibility, Day 0).
5. Female subjects of childbearing potential are eligible for the study but should be willing to use adequate (at least 1 form of) contraceptive methods as described below during the study treatment period plus 7 days (starting from the first dose of study drug and ending 7 days after the last dose of study drug).
Male subjects with partners of childbearing potential must agree to use adequate (at least 1 form of) contraception as described below during the study treatment period plus 7 days (starting from the first dose of study drug and ending 7 days after the last dose of study drug).
- Acceptable contraceptive methods for female subjects (need at least one):
o Hormonal methods of contraception (including oral and transdermal contraceptives, injectable progesterone, progestin subdermal implants, progesterone-releasing intrauterine devices [IUDs]) initiated at least 14 days prior to the first dose of study drug
o True abstinence: when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
o Placement of a copper-containing IUD
o Condom with spermicidal foam/gel/film/cream/suppository
o Postmenopausal at least 12 months (365 days) prior to the first dose of study drug or permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy)
o Male partner who has had a vasectomy for at least 3 months (90 days) prior to the first dose of study drug or is surgically sterile
- Acceptable contraceptive methods for male subjects with partners of childbearing potential (need at least one):
o True abstinence: when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
o Vasectomy for at least 3 months (90 days) prior to the first dose of study drug or surgically sterile
o Without a vasectomy, must use a condom with spermicidal foam/gel/film/cream/suppository
Ocular Inclusion Criteria
6. Subjects must have a diagnosis of OAG (including pigmentary or pseudoexfoliative) or OHT in 1 or both eyes.
7. Subjects must meet the following IOP requirements at Visit 3 (Eligibility, Day 0 [after washout for the subjects currently under treatment with an IOP-lowering medication]):
- mean/median IOP ≥ 26 mmHg at a minimum of 1 time point, ≥ 24 mmHg at a minimum of 1 time point, and ≥ 22 mmHg at 1 time point in the same eye, and
- IOP ≤ 36 mmHg at all 3 measurement time points in both eyes.
8. Subjects with a best-corrected visual acuity (BCVA), using the Early Treatment of Diabetic Retinopathy Study (ETDRS) protocol, of +0.7 logMAR units (Snellen equivalent of approximately 20/100) or better in either eye. |
|
| E.4 | Principal exclusion criteria |
1. Subjects participating in any drug or device clinical investigation within 30 days prior to Visit 1 (Screening) for subjects who require a washout period or 30 days prior to Visit 3 (Eligibility, Day 0) for subjects who do not require a washout period.
2. Subjects who are known to have been exposed to BOL-303259-X (formerly identified as NCX 116 and PF-03187207) in any previous clinical investigation prior to Visit 1 (Screening).
3. Subjects who anticipate participating in any other drug or device clinical investigation within the duration of this study.
4. Female subjects who are pregnant or breastfeeding.
5. Subjects with a history or presence of any of the following:
− Severe dysfunction of the liver or the kidneys
− Wasting disease
− Angina pectoris not controlled by medical or surgical treatment
− Severe asthma
− Hematological diseases such as aplastic anemia, pancytopenia, or hemolytic icterus
− Second or third degree atrioventricular block
− Overt cardiac failure
− Cardiogenic shock
6. Subjects with a current diagnosis of cancer.
7. Subjects with a history or presence of chronic generalized systemic disease that the Investigator feels might increase the risk to the subject or confound the results of the study.
8. Subjects with known or suspected drug or alcohol abuse.
Drug Therapies
9. Subjects with an anticipated need to initiate or modify medication (systemic or topical) that is known to affect IOP (eg, beta-adrenergic antagonists, alpha-adrenergic agonists, calcium channel blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II receptor blockers) during the first 3 months (90 days) of study treatment.
10. Subjects for whom concomitant use of medications may interact with the safety or efficacy of a nitric oxide (NO)-donating compound (eg, vasodilators such as Isordil® and BiDil®).
11. Subjects with known hypersensitivity or contraindications to latanoprost, NO treatment, or any of the ingredients in the study drugs.
12. Subjects with known hypersensitivity or contraindications to timolol maleate, other beta-adrenergic receptor antagonists, or any of the ingredients in the study drugs.
13. Subjects who are expected to require treatment with ocular or systemic corticosteroids during the first 3 months (90 days) of the study.
14. Subjects who are currently taking diclofenac (oral or topical) or who are expected to require treatment with diclofenac (oral or topical) during the first 3 months (90 days) of the study.
15. Subjects who are in need of or expected to require any other topical or systemic treatment of OAG or OHT during the study duration.
Ocular exclusion criteria:
16. Subjects who are unable to discontinue contact lens use during and for 15 minutes following instillation of study drug and during study visits.
17. Subjects who are unable to discontinue other eye drop medications such as artificial tears for 15 minutes prior to and 15 minutes after instillation of study drug.
18. Subjects with a central corneal thickness greater than 600 μm in either eye.
19. Subjects with any condition that prevents reliable applanation tonometry (eg, significant corneal surface abnormalities) in either eye.
20. Subjects with advanced glaucoma with a cup/disc ratio greater than 0.8, a history of split fixation, or a field loss threatening fixation in either eye.
21. Subjects with any condition that prevents clear visualization of the fundus in either eye.
23. Subjects with traumatic rupture of the posterior capsule in either eye (surgical or Nd:YAG laser capsulotomy is acceptable).
24. Subjects with aphakia in either eye.
25. Subjects with previous or active corneal disease in either eye.
26. Subjects with current or a history of severe dry eye in either eye.
27. Subjects with current or a history of optic disc hemorrhage in either eye.
28. Subjects with current or a history of central/branch retinal vein or artery occlusion in either eye.
29. Subjects with current or a history of macular edema in either eye.
30. Subjects with very narrow angles (3 quadrants with less than Grade 2 according to Shaffer's anterior chamber angle grading system) and subjects with angle closure, congenital, and secondary glaucoma, and subjects with history of angle closure in either eye.
31. Subjects with a diagnosis of a clinically significant or progressive retinal disease (eg, diabetic retinopathy, macular degeneration) in either eye.
32. Subjects with any intraocular infection or inflammation in either eye within 3 months (90 days) prior to Visit 1 (Screening).
Surgery
33. Subjects with a history of ocular laser surgery in either eye within the 3 months (90 days) prior to Visit 1 (Screening).
34. Subjects with a history of incisional ocular surgery or severe trauma in either eye within 3 months (90 days) prior to Visit 1 (Screening). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
The primary efficacy endpoint is the IOP in subjects’ study eye
measured at the specified time points: 8 AM, 12 PM, and 4 PM at Visit 4
(Week 2), Visit 5 (Week 6), and Visit 6 (Month 3).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy evaluations will be made at Visit 4 (Week 2), Visit 5
(Week 6), and Visit 6 (Month 3), with ongoing safety evaluations
made at Visits 7, 8, and 9 (Months 6, 9, and 12, respectively). |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints
• Proportion of subjects with I OP ≤ 1 8 m mHg consistently at all
9 time points in the first 3 months
• Proportion of subjects with IOP reduction ≥ 25% consistently at
all 9 time points in the first 3 months
Additional Secondary Efficacy Endpoints
• Change from baseline (CFB) in IOP at specified time points
(8 AM, 12 PM, and 4 PM) at Visits 4, 5, and 6 (Week 2, Week 6,
and Month 3, respectively)
• Absolute and CFB in diurnal IOP at each post-randomization visit
(Visits 4, 5, 6, 7, 8, and 9 [Week 2, Week 6, Month 3, Month 6,
Month 9, and Month 12, respectively])
• Absolute and CFB in IOP at the specified time points: 8 AM,
12 PM, and 4 PM at Visit 7 (Month 6), Visit 8 (Month 9), and
Visit 9 (Month 12)
• Standardized IOP area under the curve (AUC) (the AUC divided
by the time period that the subject was observed) by treatment
group from 8 AM at Visit 4 (Week 2) to 4 PM at the following
visits: Visit 4 (Week 2), Visit 5 (Week 6), Visit 6 (Month 3),
Visit 7 (Month 6), Visit 8 (Month 9), and Visit 9 (Month 12)
• For the timolol maleate 0.5% BID group (ie, the group of subjects
randomized to timolol maleate 0.5% BID at Visit 3 [Eligibility,
Day 0]), change in IOP from Visit 6 (Month 3) at each time point
at Visit 7 (Month 6), Visit 8 (Month 9), and Visit 9 (Month 12)
• For the timolol maleate 0.5% BID group (ie, the group of subjects
randomized to timolol maleate 0.5% BID at Visit 3 [Eligibility,
Day 0]), change in diurnal IOP from Visit 6 (Month 3) at Visit 7
(Month 6), Visit 8 (Month 9), and Visit 9 (Month 12 )
Safety Endpoint
The safety endpoint of this study is the incidence of ocular and
systemic adverse events (AEs). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy evaluations will be made at Visit 4 (Week 2), Visit 5
(Week 6), and Visit 6 (Month 3), with ongoing safety evaluations
made at Visits 7, 8, and 9 (Months 6, 9, and 12, respectively). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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